As populations age neurodegenerative disorders such as Alzheimer's disease become more prevalent. Alzheimer's disease is a common form of dementia, and is progressive and irreversible. The pathogenesis of the disease is thought to involve cerebral deposits of aggregated amyloid β-peptide. The first (and rate-limiting) step in the generation of amyloid β-peptide is cleavage of amyloid precursor protein by β-secretase (β-site amyloid precursor protein cleaving enzyme-1, β-secretase-1, hereinafter “BACE-1”). This makes BACE-1 an attractive target for new Alzheimer's therapies.
Heparan sulfate (HS) and its highly sulfated analogue heparin have been shown to inhibit BACE-1 activity. HS and heparin are both glycosaminoglycans comprising 1,4-linked disaccharide units of β-D-iduronic acid or α-L-iduronic acid with N-acetyl-α-D-glucosamine (dominant in the case of HS) or N-sulfo-α-D-glucosamine (dominant in the case of heparin) and additional O-sulfate ester substituents. Heparin is a well-known pharmaceutical with anti-coagulant activity. However, the anti-coagulant properties of heparin need to be attenuated if it is to be used for other pharmaceutical applications otherwise possible side effects, such as internal bleeding and impaired blood clotting, can be problematic.
Turnbull et al. have examined the activities of modified heparins against BACE-1 (S. J. Patey, E. A. Edwards, E. A. Yates, J. E. Turnbull, J. Med. Chem. 2006, 49, 6129-6132). They found that, after porcine mucosal heparin (PIMH), the next most effective inhibitor was a modified PIMH which had undergone N-desulfation and N-re-acetylation. Turnbull et al. also reported the preparation of oligosaccharides by enzymatic digestion of PIMH, and the activities of these oligosaccharides against BACE-1 were also determined. They found that the decasaccharide fraction was about 40-fold less active than PIMH, and the octasaccharide fraction was 10-fold less active than the decasaccharide fraction. Oligosaccharides containing 18 saccharide units were about as active as PIMH itself. As these oligosaccharide fractions are derived from a very complex polymer, the derived fractions are not single chemical species.
WO 2007/138263 describes a study by Scholefield et al., that showed that an N-acetylated heparin which is highly sulfated at the 2-O and 6-O positions is active against BACE-1 and that removal of the 2-O or 6-O sulfates decreased the activity against BACE-1. WO 2007/138263 suggests that removal of one or more sulfates would therefore be expected to have a deleterious effect on the activity. WO 2007/138263 describes and claims such de-sulfated oligosaccharides. WO 2007/138263 further states that neither N- nor 2-O-sulfation is an absolute requirement for high level activity when accompanied by 6-O sulfation. As these oligosaccharide fractions are derived from a very complex polymer, the derived fractions are not single chemical species.
WO 2010/029185 describes oligosaccharides, including decasaccharides and octasaccharides, which are said to be heparan sulfate mimetics and useful in the treatment of cancer, pathological angiogenesis and/or for inducing hematopoietic stem cell mobilisation. These oligosaccharides have an L-iduronic acid moiety at the non-reducing terminus.
There is a need for further oligosaccharides which are inhibitors of BACE-1. Furthermore, if such oligosaccharides were synthetic, in other words, if they could be synthesised de novo, they would, advantageously, be well-characterised single chemical entities. This would make them attractive for use as pharmaceuticals.
It is therefore an object of the present invention to provide oligosaccharide compounds that are inhibitors of BACE-1, or to at least provide a useful choice.